The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.

HumanizedMotorFunctionMotor function scores of wild-type and Thy1-aSyn mice colonized with fecal microbes derived from Parkinson's disease patients or matched healthy controls.MouseTreatmentMotorFunctionMotor function scores of wild-type and Thy1-aSyn mice, under differing microbial colonization status. Conventionally colonized, germ-free, antibiotic-treated, recolonized germ-free, and short-chain fatty acid treated animals.SynucleinandInflammationExpression and production of alpha-synuclein and proinflammatory cytokines, and microglia diameter and cytokine expression in the brain of wild-type and Thy1-aSyn mice, under specific pathogen free and germ-free conditions.